Salts of 1, 1-dimethyl-3-pyrrolidyl phenyl-2-thienylglycolate



United States Patent Office,

3,138,614 Patented June 23, 1964 3,138,614 SALTS OFLI-DIMETHYL-S-PYRROLIDYL PHENYL-Z-THIENYLG'LYCOLA'IE Cameron Ainsworthand Charles W. Ryan, Indianapolis, Ind, assignors to Eli Lilly andCompany, Indianapolis, Ind., a corporation of Indiana No Drawing. FiledDec. 18, 1961, Ser. No. 160,308 4 Claims. (Cl. 260-326.3)

wherein the various substituent groups are as follows:

R is a lower alkyl radical having from 1 to 4 carbon atoms.

R and R are hydrogen or lower alkyl radicals having from 1 to 4 carbonatoms, substituted at positions 2, 4, or 5, of the pyrrolidine ring.Where R and R are both alkyl radicals, both can be at one position,viz., position 2, 4, or 5 or they can be at different positions.

The lower alkyl radicals referred to hereinabove can be methyl, ethyl,n-propyl, isopropyl, n-butyl, l-methylpropyl, isobutyl, or t-butyl.

R is phenyl, chlorophenyl, bromophenyl, methoXyphenyl, thienyl, or acycloalkyl radical having from 5 to 7 carbon atoms.

From the foregoing, it will be apparent that the pyrrolidine ring canhave zero, one, or two alkyl substituents.

The pyrrolidyl esters represented by the above formula are generallycolorless liquids soluble in most organic solvents but relativelyinsoluble in water. Among such esters are the following:

1-methyl-3-pyrrolidyl bis (2-thienyl glycolate 1-ethyl-3-pyrrolidylphenyl-2-thienylglycolate l-n-propyl-3-pyrrolidylo-chlorophenyl-Z-thienylglycolate l-isopropyl-3-pyrrolidylp-bromophenyl-3-thienylglycolate 1-n-butyl-3-pyrrolidylm-methoxyphenyl-Z-thienylglycolate 1-isobutyl-3-pyrrolidylcyclopentyl-Z-thienylglycolate 1-sec-butyl-3-pyrrolidylcycloheXyl-3-thienylglycolate 1-tert-butyl-3-pyrrolidylcycloheptyl-2-thienylglycolate 1,5-dimethyl-3-pyrrolidylphenyl-2-thienylglycolate 1,2,2-trimethyl-3-pyrrolidylphenyl-2-thienylglycolate 1,4-dimethyl-3-pyrrolidylphenyl-Z-thienylglycolate l-tert-butyl-3-pyrrolidylbis(2-thienyl)glycolate 1-methyl-5-n-propyl-3-pyrrolidyl bis(2-thienyl)glycolate 1-methyl-S-isopropyl-B-pyrrolidyl phenyl-3-thienylglycolate1-methyl-5-tert-butyl-3-pyrrolidyl bis(3-thienyl) glycolate Preferredcompositions of the present invention have R and R chosen from hydrogen,methyl, and ethyl, attached to the pyrrolidine ring at the 2 and/ or 5positions, with either phenyl or thienyl in the R position. Among suchcompositions are 1-methyl-3-pyrrolidyl phenyl-2- thienylglycolate,1,5-dimethyl-3-pyrrolidyl bis(2-thienyl)- glycolate,1,5,5-trimethyl-3-pyrrolidyl phenyl-S-thienylglycolate, and1,2-dimethyl-3-pyrrolidyl bis(3-thienyl)gly colate.

Also included within the scope of this invention are the acid additionsalts (e.g., the hydrochloride, the hydrobromide, the sulfate, thephosphate, and the like) of the pyrrolidyl esters represented by theabove formula, as Well as the quaternary compounds derivable therefrom.The said quaternary compounds can be represented by the followingformula:

0 thienyl wherein R, R R and R are in accordance with the abovedefinitions thereof, R is methyl or ethyl, and X- is a pharmaceuticallyacceptable anion such as hydroxide, chloride, bromide, iodide, sulfate,nitrate, phosphate, or the like.

Presently preferred quaternary compounds coming within the ambit of thisinvention include 1-methyl-3-pyrrolidyl phenyl-2-thienylglycolatemethobromide, l-methyl- 3-pyrrolidyl phenyl-Z-thienylglycolatemethochloride, 1- methyl-3-pyrrolidyl phenyl-2-thienylglycolateethochloride, 1,5-dimethy1-3-pyrrolidyl bis(2-thienyl)glycolatemethosulfate, 1,5,5-trimethyl-3-pyrrolidyl phenyl-3-thienylglycolateethophosphate, 1,2-dimethyl-3-pyrrolidyl bis(3-thienyl)glycolatel-rnethyl hydroxide, and the like.

The alkyl-substituted 3-pyrrolidyl esters are prepared, generallyspeaking, by the reaction of the appropriate alkyl-substituted3-pyrrolidinol with a lower alkyl ester of an u-hYdIOXY a-thienylcarboxylic acid having the required R substitutent.

The alkyl-substituted 3-pyrrolidinol compounds can be prepared employingan appropriate substituted diester of a dicarboxyalkylamine and sodiumhydride in a Dieckman cyclization reaction followed successively bydecarboxylation and reduction of the ketone produced thereby.Concentrated hydrochloric acid can be employed as the decarboxylatingagent and lithium aluminum hydride or sodium borohydride as the reducingagent. The following illustration of the procedure, hereinafter referredto as Pyrrolidinol Procedure I, shows the preparation of 1-methy1-3-pyrrolidinol OH Liam, L L 002+ CzH OII N (EH,

Alternatively, the alkyl-substituted 3-pyrrolidinols can be prepared bythe reaction of the appropriate dihalo monohydroxy alkanol and amine asdescribed by Lunsford in US. Patent No. 2,830,997 (April 15, 1958),e.g., in Example 1 thereof, in which n-butylamine and 1,4-dibromo-Z-butanol are reacted to provide N-butyl-3-pyrrolidinol. Thisalternative procedure is hereinafter referred to as PyrrolidinolProcedure II.

In the preparation of the esters of alkyl-substituted 3- pyrrolidinols,an appropriate alkyl-substituted 3-pyrrolidinol and a lower alkyl esterof an oc-hYdiOXY u-thienyl carboxylic acid having the desired Rsubstituent are added in about equimolar quantities to an inert mutualsolvent, for example, n-heptane. The mixture is heated to refluxtemperature, at which time a small quantity of a basic catalyst such assodium methylate is desirably added, and refluxing is continued.Customarily, a reflux period of about three hours is sufiicient tocomplete the reaction. It has been found desirable to remove the simplealcohol by-product as it is formed, suitably by incorporating aDean-Stark trap in the reflux apparatus. The resulting alkyl-substituted3-pyrrolidyl ester can be recovered from the reaction mixture as one ofits acid addition salts by extracting the reaction mixture with anaqueous solution of the appropriate acid. The acid addition salt of theester can be obtained in crude form by evaporating the aqueous extractthereof to dryness.

The acid addition salt can be further purified if desired byreconverting the salt to the free ester, dissolving the free ester in aninert solvent such as ethyl acetate, and reprecipitating the ester asits acid addition salt, e.g., by adding an anhydrous ethanolic solutionof hydrogen chloride. The free ester can then be obtained if desired bybasifying an aqueous solution of the acid addition salt with a suitablebase such as potassium carbonate, and then extracting the basifiedmixture with a water-immiscible solvent in which the free base issoluble, such as benzene, chloroform, or ether. The organic solventextract of the free base is washed thoroughly with water and dried, andthe base is recovered from the dried extract by evaporating ordistilling the solvent.

The quaternary derivatives (e.g., the methobromide salts) of the variousalkyl-substituted 3-pyrrolidyl esters can be obtained by dissolving aquantity of the appropriate ester base in an inert mutual solvent suchas benzene or methyl ethyl ketone and introducing the appropriatequaternary salt-forming agent into the solution, e.g., methyl bromide,methyl chloride, ethyl iodide, methyl sulfate, or the like. The reactionis preferably carried out under anhydrous conditions, and generally goesforward at ordinary temperatures. Occasionally, the desired quaternarysalt precipitates as a gummy solid, in which event a Water-miscibleorganic solvent such as ethanol can be added to dilute the reactionmixture, thereby usually causing the gummy solid to convert to acrystalline white solid of the desired quaternary salt. The quaternarysalt can be recrystallized as desired from, for example, absoluteethanol.

The quaternary derivatives of the alkyl-substituted 3- pyrrolidyl estersof this invention are useful as antisecretory agents, as shown instandard animal tests such as the Shay rat test. For this purpose, thecompounds can suitably be administered orally in filled gelatin capsulesor as pressed tablets prepared with the customary fillers (lactose,glucose, starch, or the like), binding agents, stabilizing agents,lubricants, and flavors as desired. The compounds are effective at adosage level between 0.1 and mg. per kg. of body weight in the dog, andat higher levels, of the order of 10 to 50 mg. per kg, in the rat.

Furthermore, a number of the quaternary compounds of this invention areuseful as antiperspirant agents when applied topically to the loci to betreated. For this purpose, the compounds can be employed as an aqueousor an alcoholic mixture, suitably in a weight concentration of around0.5 to 5 percent, or as a solid cream containing around 0.1 to 5 percentby weight of the quaternary compound, preferably in each case in theform of a salt.

The free bases of the alkyl-substituted 3-pyrrolidyl esters are usefulas intermediates in the preparation of the quaternary compounds of thisinvention. Moreover, they have antisecretory activity, like thequaternary compounds, but are of somewhat less potency. The acid addi-1-Methyl-3-Pyrr0lidylPhenyI-Z-Thienylglycolate A solution of 5 g. ofl-methyl-3-pyrrolidinol and 12.5 g. of methyl phenyl-Z-thienylglycolatein 200 ml. of nheptane is heated to reflux temperature, a trace ofsodium methylate is added, and refluxing of the mixture is continued forthree hours. A Dean-Stark trap is incorporated in the reflux apparatusto separate and withdraw the methanol produced by the reaction. At theend of the reflux period, the reaction mixture is cooled and extractedtwo times with -ml. portions of 2 N hydrochloric acid. The acid extractsare combined, basified with potassium carbonate, and extracted threetimes with SO-ml. portions of benzene. The benzene extracts arecombined, washed two times with 25-ml. portions of water, and dried. Thebenzene is removed from the dried extract by evaporation at reducedpresure. The residue is l-methyl-3-pyrrolidyl phenyl-Z-thienylglycolatein the form of a clear liquid.

EXAMPLE 2 1-Metlzyl-3-Pyrr0lidyl Phenyl-Z-Thienylglycolate Hydrochloride1-methyl-3-pyrrolidyl phenyl-Z-thienylglycolate, prepared as describedin Example 1, is dissolved in ethyl acetate to a concentration of about20 percent by weight. To the solution is added a small excess of ananhydrous ethanolic solution of hydrogen chloride, whereupon 1-methyl-3-pyrrolidyl phenyl-Z-thienylglycolate hydrochloride separates asa white crystalline solid and is removed by filtration.

EXAMPLES 3-5 1-Methyl-3-Pyrr0lidyl Plzenyl-2-Thienylglyc0late AcidAddition Salts The hydrobromide, the sulfate, and the succinate acidaddition salts of 1-methyl-3-pyrrolidyl phenyl-Z-thienylglycolate areprepared according to the procedure of Example 2, employing hydrogenbromide, sulfuric acid, and succinic acid, respectively, instead ofhydrogen chloride.

EXAMPLE 6 1-Methyl-3-Pyrr0lidyl Phenyl-Z-Thienylglycolate MethobromideFive grams of 1-methyl-3-pyrrolidyl phenyl-Z-thienylglycolatehydrochloride, prepared as described in Example 2, are dissolved in 50ml. of water. The aqueous solution is basified by adding solid potassiumcarbonate with stirring, and the basified mixture is extracted threetimes with 25-ml. portions of benzene. The benzene extracts arecombined, dried with anhydrous magnesium sulfate, and evaporated todryness. The residue is dissolved in methyl ethyl ketone. Into theresulting solution is bubbled an excess amount of methyl bromide, andthe mixture is permitted to stand at room temperature, whereupon a Whiteprecipitate appears, consisting of 1- methyl-3-pyrrolidylphenyl-Z-thienylglycolate methobromide. The precipitate is removed byfiltration, washed with methyl ethyl ketone, recrystallized fromabsolute ethanol, and dried.

EXAMPLE 7 Diastereoisomers 0f 1-Methyl-3-Pyrrolidyl Phenyl-Z-Thienylglycolate Methobromide 1-methyl-3-pyrro1idy1phenyl-Z-thienylglycolate methobromide is readily separated into twodiastereoisomeric fractions by fractional crystallization. The crudemixed material, prepared as described in Example 6, is dissolved in theminimum quantity of methanol, decolorized with charcoal, diluted with 4or 5 volumes of ethyl acetate, concentrated on a steam bath untilcrystals begin to appear, and cooled. The resulting crystals are thealpha diastereoisomer, melting at 210-211 C.

Analysis.-Calcd. for C17H19NO3S'CH3BII C, 52.43; H, 5.38. Found: C,52.16; H, 5.54.

The mother liquor is further diluted with an equal volume of ethylacetate, concentrated on a steam bath until crystallization begins, andcooled. The resulting crystals, are the beta diastereosiomer, melting at182-184 C.

Analysis.Calcd. for C H NO S-CH B1: C, 52.43; H, 5.38. Found: C, 52.38;H, 5.43.

The alpha and beta diastereoisomers have dilferent crystal forms anddifferent infrared absorption spectra.

EXAMPLE 8 1-Methyl-3-Pyrr0lidyl Phenyl-Z-Thienylglyc0late QuaternarySalts The ethiodide, the methochloride, and the methyl methosulfatequaternary salts of l-methyl-B-pyrrolidyl phenyl-Z-thienylglycolate areprepared according to the procedure of Example 6, employing ethyliodide, methyl chloride, and methyl sulfate, respectively, instead ofmethyl bromide.

EXAMPLES 9-12 I-Ethyl-S-Pyrrolidyl Phenyl-Z-Thienylglycolate andDerivatives Ethylamine and 1,4-dichloro-2-butanol are reacted accordingto Pyrrolidinol Procedure II, described hereinabove, to produce1-ethyl-3-pyrrolidinol. The latter is reacted in equimolar ratio withmethyl phenyl-Z-thienylglycolate according to the procedure of Example 1to produce l-ethyl-3-pyrrolidyl phenyI-Z-thienylglycolate as a clearliquid product.

The resulting product is converted via the procedure of Example 2 intol-ethyl-3-pyrrolidyl phenyl-Z-thienylglyl lcolate hydrochloride in theform of a white crystalline so 'd.

Into a solution of l-ethyl-3-pyrrolidyl phenyl-2-thienylglycolate inmethyl ethyl ketone is bubbled an excess of methyl bromide. Theresulting precipitate of l-ethyl-3- pyrrolidyl phenyl-Z-thienylglycolatemethobromide is filtered off, washed with methyl ethyl ketone, andrecrystalllidzed from absolute ethanol as a white, crystalline so 1l-ethyl-3-pyrrolidyl phenyl-2-thienylglycolate ethobromide is preparedaccording to the same procedure, employing ethyl bromide instead ofmethyl bromide.

EXAMPLES 13 AND 14 1-Methyl-3-Pyrr0lidyl Cyclohexyl-Z-Thienylglycolateand Methobromide l-methyl-S-pyrrolidyl cyclohexyl-2-thienylglycolate isprepared and isolated as a clear liquid by the procedure of Example 1,employing l-methyl-3-pyrrolidinol and methylcyclohexyl-Z-thienylglycolate in equimolar ratio as the reactants.

The resulting product is converted into 1-methyl-3-pyrrolidylcyclohexyl-Z-thienylglycolate methobromide by reaction with methylbromide according to the procedure of Example 6.

EXAMPLES 15-17 1-n-Butyl-3-Pyrrolidyl Cyclopentyl-3-Thienylglycolate andDerivatives l-n-butyl-3-pyrrolidyl cyclopentyl-3-thienylglycolate isprepared and isolated as a clear liquid by the procedure of Example 1,employing 1-n-butyl-3-pyrrolidinol and methylcyclopentyl-3-thienylg1ycolate in equimolar ratio as the reactants.

The resulting product is converted into l-n-butyl-3-pyrrolidylcyclopentyl-3-thienylglycolate hydrochloride in the form of a white,crystalline solid by reaction with hydrogen chloride according to theprocedure of Example 2.

The hydrochloride is converted into 1-n-butyl-3-pyrrolidylcyclopentyl-3-thienylglycolate methobromide by reaction with methylbromide according to the procedure of Example 6.

EXAMPLES 18 and 19 1,5-Dimethyl-3-Pyrrolidyl Bis(2-Thienyl) Glycolateand Methobromide l,5-dimethyl-3-pyrrolidyl bis(2-thienyl)glycolate isprepared and isolated by the procedure of Example 1, employing1,5-dimethyl-3-pyrrolidinol and methyl bis(2- thienyl)glycolate inequimolar ratio as the reactants. The 1,5-dimethyl-3-pyrrolidinolemployed in the reaction is obtained by the reaction ofN-carbethoxymethyl-N-(Z- carbethoxypropyl)methylamine and sodium hydridefollowing Pyrrolidinol Procedure I, described hereinabove.

The resulting product is converted into the corresponding methobromideby reaction with methyl bromide according to the procedure of Example 6.

EXAMPLE 20 1,5,5-Trimethyl-3-Pyrrolidyl Phenyl-Z-Thienylglycolatel,5,5-trimethyl-3-pyrrolidyl phenyl-Z-thienylglycolate is prepared andisolated by the procedure of Example 1, employing 1,5,5-trimetl1yl-3-pyrrolidinol and methyl phenyl-2-thienylglycolate inequimolar ratio as the reactants. The l,5,5-trimethyl-3-pyrrolidinolemployed in the reaction is prepared by the reaction ofa,a-dimethyl-fi-carbethoxyethyl-a-carbethoxymethylmethylamine and sodiumhydride following Pyrrolidinol Procedure I.

EXAMPLE 21 1,2-Dimethyl-S-Pyrrolidyl Phenyl-Z-Thienylglycolate 1,2dimethyl-3-pyrrolidyl phenyl-2-thienylglycolate is prepared and isolatedby the procedure of Example 1, employing 2.0 g. of1,2-dimethyl-3-pyrrolidinol and 5.2 g. of methylphenyl-Z-thienylglycolate as the reactants.

EXAMPLE 22 1,2,2-Trimethyl-3-Pprr0lidyl Phenyl-Z-Thienylglycolate1,2,2-trimethyl-3-pyrrolidyl phenyl-Z-thienylglyoolate is prepared andisolated by the procedure of Example 1, employing 3.0 g. ofl,2,2-trimethyl-3-pyrrolidinol and 6.3 g. of methylphenyl-Z-thienylglycolate as the reactants.

EXAMPLE 23 1,4-Dimethyl-3-Pyrrolidyl Phenyl-Z-Thienylglyc0late1,4-dimethyl-3-pyrrolidyl phenyl-Z-thienylglycolate is prepared andisolated by the procedure of Example 1, employing 1.0 g. of1,4-dimethyl-3-pyrrolidinol and 2.7 g. of methylphenyl-2-thienylglycolate as the reactants.

EXAMPLES 24-27 Methobromides The phenyl-2-thienylglycolate esters ofExamples 20 23 are converted into the corresponding methobromides byreaction with methyl bromide according to the procedure of Example 6.

While the foregoing description represents certain specific embodimentsof the invention, it is to be understood that such matters areillustrative only and not by way of limitation. Numerous modificationsand equivalents of the invention will be readily apparent to thoseskilled in the art from the foregoing description.

We claim:

1. 1 methyl 3-pyrrolidyl phenyl-Z-thienylglycolate methobromide.

2. The alpha diastereoisomer of l-methyl-3-pyrrolidylphenyl-Z-thienylglycolate methobromide.

:3. The beta diastereoisomer of l-methyl-3-pyrrolidylphenyl-2-thienylglycolate methobromide.

7 4. A salt of 1,1-dimethyl-3-pyrrolidy1 phenyl-Z-thienyl FOREIGNPATENTS glycolate with a pharmaceutically acceptable acid. 799,778 GreatBritain Aug 13 1958 References Cited in the file of this patent 821,436Great Britain Oct. 7, 1959 2,928,843 Mehta et a1. Mar. 15, 19602,956,062 Lunsford Oct. 11, 1960 2 13 3" chem' vol-774112250 and2,980,693 Cavalla Apr. 18, 1961 2,995,560 Biel Aug. 8, 1961

4. A SALT OF 1,1-DIMETHYL-3-PYRROLIDYL PHENYL-2-THIENYLGLYCOLATE WITH APHARMACEUTICALLY ACCEPTABLE ACID.